Illustrative examples of diffusional drug delivery device are found in U.S. Pat. Nos. 3,598,122 and 3,948,262 to Zaffaroni and 4,379,454 to Campbell et al, which are incorporated herein by reference. In these devices a drug or other active agent is released by diffusion from a reservoir through the agent releasing surface of the device to the biological environment at which the device is applied. Such devices perform well in the administration of many agents but are not suitable for the administration of an agent whose dosage regime requires that the onset of therapeutic effect be delayed for a significant period of time after application of the device at the site of delivery. This is because the surface through which the agent is released, at the time of application, contains the agent in an amount that is significant compared to the amount in the body that gives rise to a therapeutic concentration. In those devices which utilize an agent reservoir which contains an agent at a concentration above the saturation concentration of the agent in the material from which the reservoir is formed, the agent will be present at the agent releasing surface at the saturation concentration of the agent in the material from which the releasing surface is formed. Saturation concentration is equivalent to a thermodynamic activity of 1 (unit activity). When prior art diffusional devices are applied, agent is immediately available for diffusion into the body and the concentration of the agent at the releasing surface rapidly decreases as the concentration gradient required for steady-state diffusional delivery is established by the absorption of the agent from the releasing surface into the body. In some cases the initial rate of release is unacceptably high and a method for reducing this initial "burst" of agent delivery is described in U.S. Pat. No. 3,923,939 to Baker et al. Even in this patent, the agent releasing surface of the diffusional embodiment contains the agent at the saturation concentration of the agent in the material in which it is dispersed and delivery commences immediately in the manner described above.
Non-diffusional devices are known which do not immediately present drug to the biological environment when installed, such as devices which contain material in breakable microcapsules, or the fluid imbibing pump described in commonly assigned U.S. Pat. No. 4,655,766, of Theeuwes, et al, filed Apr. 17, 1986 for Fluid Imbibing Pump With Self-Regulating Skin Patch. Diffusional delivery devices known to the prior art, however, do not possess this capability.
In addition to providing for a delay, there also exists a need to provide for the sequential, patterned delivery of different agents which may be required in multi-drug regimens.
Currently, oral dosage forms are prescribed in an attempt to meet complex administration objectives. This method requires a high degree of patient cooperation and discipline and often results in improper dosage. Insertable, implantable or transdermal diffusional delivery devices provide improved patient compliance and assured dosage but, for numerous reasons, have heretofore not been adaptable to complex administration of varying dosages of like or different drugs at predetermined intervals from a single delivery device.
The devices of this invention are particularly useful in providing a predetermined, delayed onset of therapeutic effect for any desired time period after application to the skin. Thus, a device could be removed and a new one applied simultaneously, wherein the desired drug-free interval is obtained.
An attempt to address the problems associated with combining different agents in one diffusional device is disclosed in U.S. Pat. No. 2,381,621 to Schmelkes which relates to a dressing for a moist lesion containing multiple medications. The medications are dispersed in separate layers of impermeable material prior to use and upon application to the lesion, the dressing rapidly absorbs water, allowing the separate layers to become permeable to the medications and promptly administering them to the lesion. The devices of Schaelkes all begin to deliver medication upon application and result in substantially concurrent, rather than sequential administration of the multiple medications.
One of the advantages of a continuous release dosage form, such as a transdermal drug delivery device, is the improvement in patient compliance that is obtained from the concurrent removal of one device and application of a new device at the same time. This advantage is lost when removal and application occur at different times or where onset of a therapeutic effect is desired at an inconvenient time such as shortly prior to arousal. It is not possible, using concurrent application and removal of diffusional delivery devices of the prior art to substantially delay the onset of transdermal drug delivery from the time of application, such as at bedtime, until shortly prior to arousal. While other, non-diffusional delivery devices exist which can deliver drug after an extended delay, diffusional devices of the prior art do not possess this capability and rapidly commence delivering the drug at their intended therapeutic rates.
It is accordingly an object of this invention to provide a diffusional agent delivery device which provides for delayed onset of agent administration.
It is another object of this invention to provide a diffusional delivery device for delivering multiple agents in a predetermined, sequential pattern of administration.
It is an additional object to provide for the maintenance of drug potency and device efficacy during prolonged storage periods, whereby the device is inactive while stored, and active when applied to the delivery site.
It is another object to provide for the preprogrammed release of a plurality of drugs, wherein the individual drugs are maintained separated.
It is yet another object of the invention to provide a diffusional delivery device which continuously releases therapeutic agent into a biological environment after a period of no drug delivery.
It is another object of this invention to provide a diffusional delivery device having at least one delay membrane which changes state after application to the site of administration to release drug at the desired rate at a predetermined interval after application.
It is another object of this invention to provide a diffusional transdermal delivery device capable of patterned delivery.